Evaluation of (64)Cu-Based Radiopharmaceuticals that Target Aβ Peptide Aggregates as Diagnostic Tools for Alzheimer’s Disease

[Image: see text] Positron emission tomography (PET) imaging agents that detect amyloid plaques containing amyloid beta (Aβ) peptide aggregates in the brain of Alzheimer’s disease (AD) patients have been successfully developed and recently approved by the FDA for clinical use. However, the short half-lives of the currently used radionuclides (11)C (20.4 min) and (18)F (109.8 min) may limit the widespread use of these imaging agents. Therefore, we have begun to evaluate novel AD diagnostic agents that can be radiolabeled with (64)Cu, a radionuclide with a half-life of 12.7 h, ideal for PET imaging. Described herein are a series of bifunctional chelators (BFCs), L(1)–L(5), that were designed to tightly bind (64)Cu and shown to interact with Aβ aggregates both in vitro and in transgenic AD mouse brain sections. Importantly, biodistribution studies show that these compounds exhibit promising brain uptake and rapid clearance in wild-type mice, and initial microPET imaging studies of transgenic AD mice suggest that these compounds could serve as lead compounds for the development of improved diagnostic agents for AD.